Sodium glucose co-transporter 2 (SGLT2) is abundantly expressed in proximal tubular cells and mediates approximately 90% of glucose reabsorption within the kidney. SGLT2 inhibitors are a new class of oral antidiabetic drugs (OADs) that specifically target glucose reabsorption in the kidney, thereby facilitating glucose excretion into urine. This removal of excess glucose from the body is associated with a reduction in blood glucose levels in patients with type 2 diabetes (T2D) [
]. Moreover, the inhibition of glucose reabsorption mediated by SGLT2 inhibitors leads to increased osmolarity within the tubular lumen. Consequently, previous clinical studies with SGLT2 inhibitors have reported that treatment initiation with this drug class induced diuresis and led to a transient increase in overall urine volume [
; Boehringer Ingelheim), a highly selective SGLT2 inhibitor [
], is approved in Europe, Japan, and the US for the treatment of hyperglycemia in patients with T2D [
]. Moreover, empagliflozin is the first OAD to demonstrate a significant reduction (of 38%) in the risk of cardiovascular (CV) death as compared to standard-of-care therapy in a large cardiovascular outcomes trial in patients with T2D and established CV disease [
]. In previous phase 2–3 clinical trials, treatment with once-daily empagliflozin significantly ameliorated hyperglycemia, irrespective of commonly used glucose-lowering background therapy, and was well tolerated overall in T2D patients, including those of Japanese ethnicity [
In a pharmacodynamic study of Caucasian patients with T2D, initiation of empagliflozin treatment led to a transient increase in 24-h urine volume [
]. However, respective data for Japanese T2D patients and further effects of empagliflozin on daily fluid intake were scarce. Therefore, in the post hoc analysis reported in the present paper, we assessed changes in 24-h urine volume, fluid intake, and fluid balance in Japanese patients with T2D after the initiation of empagliflozin treatment in a previously completed local, randomized, controlled phase 2 trial [
Since SGLT2 inhibitors induce sustained glucosuria, it has been speculated that increased osmolarity due to augmented glucose delivery to the tubular lumen of the kidneys could impact short-term and long-term whole-body fluid balance. Consequently, reports of adverse events consistent with volume depletion have emerged from clinical trials as well as the routine clinical use of SGLT2 inhibitors. We therefore assessed the acute and chronic effects of empagliflozin on 24-h urine volume production and daily fluid intake in Japanese patients with T2D using data retrieved from a previously completed phase 2, pharmacodynamic study [
Our results show that treatment initiation with empagliflozin leads to a rapid pharmacodynamic response which is reflected in a significant increase in UGE following the first intake of the study drug. This effect of empagliflozin was maintained throughout the study period, leading to stable and clinically relevant levels of glucosuria. Novel insights from this study show that patients initiated on either 10 mg or 25 mg empagliflozin presented a significant increase in 24-h urine volume on day 1. The observed increase in urine volume within the first 24 h of treatment corresponded to an average additional daily output of approximately 500–800 mL for the 10 mg and 25 mg doses of empagliflozin compared to placebo. Importantly, however, this increase in urine volume with empagliflozin was transient in nature, and returned to 24-h baseline urine levels similar to those observed in the placebo group after 4 weeks of chronic treatment. These results in Japanese patients with T2D are reminiscent of a previous study in Caucasian T2D patients treated with empagliflozin [
]. Data showed a significant increase in 24-h urine volume with empagliflozin on day 1, but urine volume returned to baseline values, with no change versus placebo as early as day 5 despite sustained glucosuria. Similar data were also reported with another SGLT2 inhibitor, canagliflozin, with an initial increase in urine volume versus placebo observed in Japanese patients with T2D treated with 25–400 mg canagliflozin on day 1; this effect disappeared as early as day 2 [
Our data address an important clinical consideration pertaining to the appropriate use of SGLT2 inhibitors in patients with T2D. Since the mechanism of action of SGLT2 inhibitors is known to induce sustained glucosuria, concerns have been raised that patients could be at increased risk of a clinically relevant loss of plasma and/or whole-body fluids, leading to volume depletion or dehydration events. Such concerns are of clinical relevance to Japanese T2D patients due to important demographic differences such as a higher average age and a lower BMI as compared to Caucasian T2D populations. The existing evidence for SGLT2 inhibitors to date, including studies in Japanese T2D patients, indicates that an increase in urine volume occurs immediately after treatment initiation (i.e., during the first 24–48 h). Hence, patients may be advised to increase fluid intake accordingly and to monitor acute changes in both urine output and body weight when starting a SGLT2 inhibitor. After this short-term initial phase of increased urine production, equilibrium is expected to be reached within the first week of SGLT2 treatment [
]. Notably, comprehensive studies of patients at increased risk for dehydration (e.g., T2D individuals > 75 years old and/or receiving concomitant diuretic therapy) are currently scarce, so careful weighing of the benefits and risks of SGLT2 inhibitors, including the clinical risk of volume changes in these patients, is warranted.
How could the transient effect of SGLT2 inhibitors on urine volume (despite the fact that glucosuria is sustained at levels of approximately 50–80 g/day [
], exerting osmotic forces along the nephron) be explained? It is tempting to speculate that there must be a holistic compensatory mechanism of the kidneys that is capable of mitigating the risk of excess whole-body fluid loss by osmotic diuresis. This hypothesis seems obvious given the central role of the kidneys in maintaining whole-body fluid and electrolyte balance. Recently, however, experimental data have permitted novel insights into the more specific nature of SGLT2 inhibitor-related adaptive responses within the kidney. In a study of Sprague–Dawley rats with streptozotocin-induced diabetes, dapagliflozin induced the expression of urea transporter A1 (UT-A1) in the inner medulla of the kidney, resulting in decreased urea excretion in the urine [
]. The authors speculate that SGLT2 inhibition may in turn increase urea levels in the medullary interstitium, which would augment outbound osmotic forces that are capable of reabsorbing free water from the tubular lumen [
]. In accordance with this hypothesis, we observed a mild increase in serum urea level with empagliflozin in our study [adjusted mean difference (95% confidence interval (CI)) versus placebo at day 28: empagliflozin 10 mg, 0.383 (0.259, 0.506) mmol/L,
< 0.0001; empagliflozin 25 mg, 0.375 (0.248, 0.502) mmol/L,
< 0.0001]. These results are in accordance with evidence from a previous Caucasian study with empagliflozin [
]. Therefore, the combined experimental and clinical data suggest that SGLT2 inhibitor-mediated osmotic diuresis could be compensated, at least in part, by an increase in the urea level and hypertonicity in the inner medulla, enabling the kidney to maintain whole-body fluid balance even under conditions of sustained glucosuria.
Although vasopressin plays a pivotal role in the regulation of urine volume [
], a previous study by Tanaka et al. showed that treatment with canagliflozin had no effect on vasopressin levels in patients [
], suggesting that the alterations in urine volume mediated by SGLT2 inhibitors could be attributed to vasopressin-independent mechanisms. Future research is needed to further decipher the nature of potential additional tubular compensatory mechanisms, including the expression and activity of transporters for solutes, electrolytes, and free water.
The strength of our study is based on its randomized, double-blind, placebo-controlled design and the consistency of findings for the 10 mg and 25 mg empagliflozin groups. Assessments of 24-h urine volume and fluid intake occurred during in-patient periods, increasing the internal validity of our findings. Limitations apply to the study population, which did not include patients at a particularly increased risk for dehydration (e.g., higher age and concomitant diuretic use). In addition, 24-h urine collections were performed on day 1 and then again after 4 weeks of treatment. Hence, it is still expected to obtain a more detailed time course for the observed adaptations in daily urine volume, especially during the first 1–2 weeks of treatment with empagliflozin in Japanese patients with type 2 diabetes.
The authors would like to thank Kazuki Koiwai for acquiring and interpreting data relating to this study.
The study, including article processing charges, was funded by Nippon Boehringer Ingelheim Co. Ltd.
Medical Writing and Editorial Assistance
Editorial support and medical writing services were provided by Varunkumar Pandey, PhD and Maribeth Bogush, PhD of Cactus Communications, and were funded by Nippon Boehringer Ingelheim Co., Ltd.
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published. All authors had full access to all the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis.
Atsutaka Yasui is an employee of Nippon Boehringer Ingelheim Co. Ltd. Ganghyuck Lee is an employee of Nippon Boehringer Ingelheim Co. Ltd. Tatsuroh Kanekol is an employee of Nippon Boehringer Ingelheim Co. Ltd. Tomoo Okamura is an employee of Nippon Boehringer Ingelheim Co. Ltd. Tetsuaki Hirase is an employee of Eli Lilly Japan K.K. Stefan Kaspers is an employee of Boehringer Ingelheim Pharma GmbH & Co. KG. Maximilian von Eynatten is an employee of Boehringer Ingelheim Pharma GmbH & Co. KG.
Compliance with Ethics Guidelines
This clinical trial (NCT00885118) was conducted in accordance with the Declaration of Helsinki (1996), the International Conference on Harmonization Good Clinical Practice guidelines, and Japanese GCP regulations. Additionally, the local ethics committee (institutional review board) approved the study protocol. Written consent was received from all participants before study commencement.
The datasets analyzed during the current study are available from the corresponding author on reasonable request.
This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (
), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.